Pain has been defined in a variety of ways. For example, pain can be defined as the perception by a subject of noxious stimuli that produces a withdrawal reaction by the subject. The most commonly experienced form of pain may be defined as the effect of a stimulus on nerve endings, which results in the transmission of impulses to the cerebrum. This somatic sensation and normal function of pain, referred to as nociception or nociceptive pain, informs the organism of impending tissue damage. Somatic and visceral free nerve endings, termed nociceptors, initially process such pain signals.
Pain is a subjective experience related to perception of inputs to the central nervous system by a specific class of sensory receptors known as nociceptors. Nociceptors fire in response to noxious thermal, mechanical and chemical stimuli. Coding of a stimulus as painful occurs at several levels in the nervous system. The first is at the level of transduction of the noxious stimulus in the peripheral nerve terminals of the nociceptors. During the transduction step, the noxious stimulus is converted to an electrical stimulus in the form of an action potential. In mammals the vanilloid receptors (VR-1 and VRL-1) are proposed to function during transduction of a noxious heat stimulus. Candidate molecules for transducing noxious mechanical stimuli have yet to be identified.
The second level of coding occurs in the dorsal horn of the spinal cord. The cell bodies of nociceptive neurons are found in the dorsal root ganglia and send projections both to the periphery and to the dorsal horn. Upon stimulation nociceptors release the excitatory neurotransmitter glutamate which produces action potential sin post-synaptic cells of the dorsal horn, which project to the brain where pain is perceived. The higher level processing involved in pain perception are poorly understood. High intensity pain is signaled through increased release of substance P by the afferent nociceptive terminals in the dorsal horn. This peptide function through the G-protein couples substance P receptor, NK-1.
In general, while brain pathways governing the perception of pain are still incompletely understood, sensory afferent synaptic connections to the spinal cord, termed “nociceptive pathways” have been studied. The nociceptive pathway, which exists for protection of the organism (such as the pain experienced in response to a burn), is inactive. Activity is initiated by the application of a high intensity, potentially damaging stimulus. This stimulus serves to depolarize certain classes of afferent (sensory) axons of the small unmyelinated category, designed C fibers.
The signal carried by the C fibers travels up the peripheral nerve and into the spinal cord where synapses are made on second order and higher order neurons, which then transmit the pain signal up the spinal cord in the spinothalamic tract ending in the thalamus. Polysynaptic junctions in the dorsal horn of the spinal cord are involved in the relay and modulation of sensations of pain to various regions of the brain, including the periaqueductal grey region. The ventrolateral and ventromedial thalamic nuclei project to the cortex where the pain is then processed with regard to localization and other integrative characteristics.
Analgesia, or the reduction of pain perception, can be affected directly by decreasing transmission along such nociceptive pathways. Analgesic opiates are thought to act by mimicking the effects of endorphin or enkephalin peptide-containing neurons, which synapse presynaptically at the C-fiber terminal and which, when they fire, inhibit release of substance P from the C-fiber. Descending pathways from the brain are also inhibitory to C-fiber firing. Thus, CNS-mediated analgesia leads to an overall inhibition of the pain transmission.
While neuropathic pain is known to have a number of underlying etiologies, it is characterized by a distinct set of symptoms. As described in greater detail below, these can include enhanced sensitivity to innocuous thermal-mechanical stimuli, abnormal sensitivity to noxious stimuli, tenderness, and spontaneous burning pain. Neuropathic pain is also progressive in nature, in that it generally worsens over time. Known treatment methods treat the symptoms without necessarily lessening the underlying pathology.
Typically, chronic nociceptive pain results from changes in the peripheral sensory terminal secondary to local tissue damage. Mild damage, such as abrasions or burns, and inflammation in the cutaneous receptive fields or joints will produce significant increases in the excitability of polymodal nociceptors (C fibers) and high threshold mechanoreceptors. This increased excitability leads to increased spontaneous activity and an exaggerated response to otherwise minimal stimuli.
These events have several consequences. First, the magnitude of the pain state in humans and animals is proportional to the discharge rate in such sensory afferent. The facilitated response secondary to the local peripheral injury may lead to an exaggerated pain state simply because of the increased afferent activity. Secondly, spontaneous activity in small sensory afferent causes central neurons in the spinal cord to develop an exaggerated response to subsequent input. Both of these events, secondary to the increased spontaneous activity and reactivity in small sensory afferent generated by the peripheral injury leads to a behavioral state referred to as hyperalgesia. Thus, where the pain response is the result of an exaggerated response to a given stimulus, the organism is hyperalgesic. The importance of the hyperalgesic state in the post injury pain state has been repeatedly demonstrated and this facilitated processing appears to account for a major proportion of the post-injury/inflammatory pain state.
Despite numerous definitions, the brain pathways, mechanisms and intermediates governing the perception of pain are not completely understood. A number of analgesics and opiates are currently on the market to address the discomforts associated with pain. However, many of these agents are addictive or have side effects that often provide additional discomforts to a subject when taken over a long period of time. For example, side effects associated with a number of opiates include sedation, depression of respiration, constipation, nausea and emesis, abuse liability and the development of addiction. These effects serve to limit the utility of opiates for controlling post injury pain. Addiction liability can occur secondary to medical uses of the drug where the central effects lead to an addicted and dependent state.
Pain is a major problem for the individual sufferer and for society because of the high costs involved in managing pain. Pain is often a part of numerous disorders or diseases including, for example, cancer pathology. Terminally ill subjects often suffer immensely because our ability to effectively manage pain is inadequate. Therefore, strategies to identify molecules that function in pain sensation are needed.